Intratumoral TREX1 Induction Promotes Immune Evasion by Limiting Type I IFN

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Chromosomal instability (CIN) is a key feature of aggressive human cancers.
• CIN can lead to cytosolic DNA accumulation, activating the cGAS-STING innate immune pathway.
• Mechanisms by which tumors with CIN evade immune surveillance are not fully understood.

Purpose of the Study:

• To investigate the role of TREX1 in managing immune responses triggered by chromosomal instability in cancer.
• To determine if TREX1 functions as a mechanism for immune evasion in chromosomally unstable tumors.

Main Methods:

• Analysis of TREX1 expression in relation to chromosomal instability and immune responses.
• Experimental manipulation of TREX1 levels in tumor models.
• Assessment of tumor growth, host survival, immune infiltration, and response to immunotherapy.

Main Results:

• cGAS-STING pathway activation leads to TREX1 upregulation, which degrades cytosolic DNA.
• Loss of TREX1 reduces tumor growth, improves host survival, and increases anti-tumor immune cell infiltration.
• TREX1 inhibition enhances responses to immune checkpoint blockade in STING-dependent tumors.

Conclusions:

• TREX1 acts as a critical negative feedback mechanism, enabling chromosomally unstable tumors to evade immune surveillance by reducing type I interferon production.
• Targeting TREX1 may offer a selective therapeutic strategy for cancers with intact STING-mediated interferon responses.